Distinct Immunoglobulin Fc Glycosylation Patterns Are Associated with Disease Nonprogression and Broadly Neutralizing Antibody Responses in Children with HIV Infection

Muenchhoff, Maximilian; Chung, Amy W.; Roider, Julia; Dugast, Anne‐Sophie; Richardson, Simone I.; Kløverpris, Henrik N.; Leslie, Alasdair; Ndung’u, Thumbi; Moore, Penny L.; Alter, Galit; Goulder, Philip

doi:10.1128/msphere.00880-20

Cited by 9 publications

(10 citation statements)

References 56 publications

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“…ADNKA, likely driven by robust IgG1 responses, is consistently observed across cohorts (379, 380), and, along with decreased Fc fucosylation, may contribute to disease control in PNP (380). Notably, coordination of Fc effector responses (379) and increased antigen-specific IgG Fc sialylation (380) were positively associated with neutralisation breadth, suggesting dual benefit to vaccines targeting the generation of Fc functional antibodies.…”

Section: Childrenmentioning

confidence: 99%

Polyfunctional antibodies: a path towards precision vaccines for vulnerable populations

et al. 2023

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Vaccine efficacy determined within the controlled environment of a clinical trial is usually substantially greater than real-world vaccine effectiveness. Typically, this results from reduced protection of immunologically vulnerable populations, such as children, elderly individuals and people with chronic comorbidities. Consequently, these high-risk groups are frequently recommended tailored immunisation schedules to boost responses. In addition, diverse groups of healthy adults may also be variably protected by the same vaccine regimen. Current population-based vaccination strategies that consider basic clinical parameters offer a glimpse into what may be achievable if more nuanced aspects of the immune response are considered in vaccine design. To date, vaccine development has been largely empirical. However, next-generation approaches require more rational strategies. We foresee a generation of precision vaccines that consider the mechanistic basis of vaccine response variations associated with both immunogenetic and baseline health differences. Recent efforts have highlighted the importance of balanced and diverse extra-neutralising antibody functions for vaccine-induced protection. However, in immunologically vulnerable populations, significant modulation of polyfunctional antibody responses that mediate both neutralisation and effector functions has been observed. Here, we review the current understanding of key genetic and inflammatory modulators of antibody polyfunctionality that affect vaccination outcomes and consider how this knowledge may be harnessed to tailor vaccine design for improved public health.

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Section: Childrenmentioning

confidence: 99%

Polyfunctional antibodies: a path towards precision vaccines for vulnerable populations

et al. 2023

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“…Recent work has highlighted a potential role for non-neutralizing HIV-specific antibodies in protection from disease progression and viral control, implicating features that could be exploited in attempts to achieve HIV cure. Muenchhoff et al described that a subset of ART-naïve children with HIV who maintained normal CD4+ T cells also known as pediatric non progressors (PNPs) had higher p24-specific IgG levels than children under ART, and these anti-p24 IgG were mostly of the IgG1 subclass ( 60 ). Meanwhile in PPs, there was a greater contribution to IgG3 subclass to the p24-specific IgG responses.…”

Section: Immune Profiles Of Pediatric and Adult Hiv Elite Controllersmentioning

confidence: 99%

“…This suggests that in PNPs viral replication is under control without chronic inflammation, while PPs have more inflammatory responses. Interestingly, when compared to uninfected children, PNPs had no changes in bulk IgG galactosylation, which corresponds to low immune activation and inflammation ( 60 ). In PPs, agalactosylated IgG glycans were expanded, while digalactosylated glycans were decreased compared to HIV-uninfected children.…”

Section: Immune Profiles Of Pediatric and Adult Hiv Elite Controllersmentioning

confidence: 99%

“…In PPs, agalactosylated IgG glycans were expanded, while digalactosylated glycans were decreased compared to HIV-uninfected children. Moreover, PNPs demonstrated increased HIV-specific Fc-mediated IgG effector functions, antibody-dependent cellular cytotoxicity (ADCC) and phagocytosis (ADCP), compared to progressors ( 60 ). Interestingly, robust ADCC ( 62 , 63 ) and overall superior polyfunctional Fc dependent activity ( 64 , 65 ) have been consistently observed in adult ECs.…”

Section: Immune Profiles Of Pediatric and Adult Hiv Elite Controllersmentioning

confidence: 99%

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Challenges and Opportunities of Therapies Targeting Early Life Immunity for Pediatric HIV Cure

et al. 2022

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Early initiation of antiretroviral therapy (ART) significantly improves clinical outcomes and reduces mortality of infants/children living with HIV. However, the ability of infected cells to establish latent viral reservoirs shortly after infection and to persist during long-term ART remains a major barrier to cure. In addition, while early ART treatment of infants living with HIV can limit the size of the virus reservoir, it can also blunt HIV-specific immune responses and does not mediate clearance of latently infected viral reservoirs. Thus, adjunctive immune-based therapies that are geared towards limiting the establishment of the virus reservoir and/or mediating the clearance of persistent reservoirs are of interest for their potential to achieve viral remission in the setting of pediatric HIV. Because of the differences between the early life and adult immune systems, these interventions may need to be tailored to the pediatric settings. Understanding the attributes and specificities of the early life immune milieu that are likely to impact the virus reservoir is important to guide the development of pediatric-specific immune-based interventions towards viral remission and cure. In this review, we compare the immune profiles of pediatric and adult HIV elite controllers, discuss the characteristics of cellular and anatomic HIV reservoirs in pediatric populations, and highlight the potential values of current cure strategies using immune-based therapies for long-term viral remission in the absence of ART in children living with HIV.

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“…HIV rebound during antiretroviral therapy (ART) is strongly associated with patients’ levels of di-galactosylated and agalactosylated IgG in two geographically distinct cohorts [ 97 , 98 ]. IgG N-glycan profiles also differed between adolescents with HIV that progressed to more severe immunocompromised states compared to HIV non-progressors [ 99 ]. Pediatric HIV non-progressors exhibited IgG Fc N-glycosylation associated with a more potent effector function.…”

Section: Igg N-glycans Altered During Infectious Diseasementioning

confidence: 99%

IgG N-glycan Signatures as Potential Diagnostic and Prognostic Biomarkers

2023

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IgG N-glycans are an emerging source of disease-specific biomarkers. Over the last decade, the continued development of glycomic databases and the evolution of glyco-analytic methods have resulted in increased throughput, resolution, and sensitivity. IgG N-glycans promote adaptive immune responses through antibody-dependent cellular cytotoxicity (ADCC) and complement activation to combat infection or cancer and promote autoimmunity. In addition to the functional assays, researchers are examining the ability of protein-specific glycosylation to serve as biomarkers of disease. This literature review demonstrates that IgG N-glycans can discriminate between healthy controls, autoimmune disease, infectious disease, and cancer with high sensitivity. The literature also indicates that the IgG glycosylation patterns vary across disease state, thereby supporting their role as specific biomarkers. In addition, IgG N-glycans can be collected longitudinally from patients to track treatment responses or predict disease reoccurrence. This review focuses on IgG N-glycan profiles applied as diagnostics, cohort discriminators, and prognostics. Recent successes, remaining challenges, and upcoming approaches are critically discussed.

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Distinct Immunoglobulin Fc Glycosylation Patterns Are Associated with Disease Nonprogression and Broadly Neutralizing Antibody Responses in Children with HIV Infection

Cited by 9 publications

References 56 publications

Polyfunctional antibodies: a path towards precision vaccines for vulnerable populations

Polyfunctional antibodies: a path towards precision vaccines for vulnerable populations

Challenges and Opportunities of Therapies Targeting Early Life Immunity for Pediatric HIV Cure

IgG N-glycan Signatures as Potential Diagnostic and Prognostic Biomarkers

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